Synthesis of the left-hand portion of geldanamycin using an anti glycolate aldol reaction.

Article abstract of DOI:10.1021/ol0068997

[figure: see text] A synthesis of the left-hand portion of the ansamycin antitumor natural product geldanamycin is reported. An advanced intermediate incorporates the methoxyquinone precursor as a pentasubstituted benzene with a 10-carbon chain that contains 4 of the 6 stereocenters. The key reaction is a novel anti glycolate aldol reaction with a new diaryl-4-oxapyrone used to generate the C-11, C-12 hydroxy, methoxy functionality.

Full text of DOI:10.1021/ol0068997

ORGANIC
LETTERS
2001
Vol. 3, No. 2
259-262
Synthesis of the Left-Hand Portion of
Geldanamycin Using an Anti Glycolate
Aldol Reaction
Merritt B. Andrus,* Erik L. Meredith, and B. B. V. Soma Sekhar
Department of Chemistry and Biochemistry, C100 BNSN, Brigham Young UniVersity,
ProVo, Utah 84602
mbandrus@chemdept.byu.edu
Received November 20, 2000
ABSTRACT
A synthesis of the left-hand portion of the ansamycin antitumor natural product geldanamycin is reported. An advanced intermediate incorporates
the methoxyquinone precursor as a pentasubstituted benzene with a 10-carbon chain that contains 4 of the 6 stereocenters. The key reaction
is a novel anti glycolate aldol reaction with a new diaryl-4-oxapyrone used to generate the C-11, C-12 hydroxy, methoxy functionality.
While the closely related anasamycin antibiotics1 macbecin
I and herbimycin have garnered considerable synthetic
attention including total syntheses,2 no efforts directed toward
the original member of the family, geldanamycin,3 have been
reported.4 These compounds possess numerous and varied
biological activities,5 including great potential as antitumor
agents. Geldanamycin, the most potent in the family, shows
broad activity with the NCI cell line panel (13 nM) and
possesses a unique mode of action.6 Details of this activity
have only recently been uncovered. Geldanamycin binds very
tightly to the ATP binding domain of the chaperone heat
shock protein 90 (Hsp90), inhibiting its protein folding
activity and ATPase activity leading to cell cycle disruption.7
(1) Rinehart, K. L. Acc. Chem. Res. 1972, 5, 57.
(2) Herbimycin A: (a) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.
Tamai, T.; Tatsuda, K. Tetrahedron Lett. 1991, 32, 6015. Nakata, M.; Osumi,
T.; Ueno, A.; Kimura, T. Tamai, T.; Tatsuda, K. Bull. Chem. Soc. Jpn.
1992, 65, 2974. Macbecin I: (b) Baker, R.; Castro, J. L. J. Chem. Soc.,
Perkin Trans. 1990, 47. (c) Evans, D. A.; Miller, S. J.; Ennis, M. D.;
Ornstein, P. L. J. Org. Chem. 1992, 57, 1067. Evans, D. A.; Miller, S. J.;
Ennis, M. D. J. Org. Chem. 1993, 58, 471. (d) Panek, J. S.; Xu, F. J. Am.
Chem. Soc. 1995, 117, 10587. Panek, J. S.; Xu, F.; Rondon, A. C. J. Am.
Chem. Soc. 1998, 120, 4413. Partial Routes: (e) Coutts, S. J.; Wittman,
M. D.; Kallmerten, J. Tetrahedron Lett. 1990, 31, 4301. (f) Coutts, S. J.;
Kallmerten, J. Tetrahedron Lett. 1990, 31, 4305. (g) Marshall, J. A.; Sedrani,
R. J. Org. Chem. 1991, 56, 5496. (h) Martin, S. F.; Dodge, J. A.; Burgess,
L. E.; Laurence, E.; Hartmeann, M. J. Org. Chem. 1992, 57, 1070. (j) Martin,
S. F.; Dodge, J. A.; Burgess, L. E.; Limberakis, C.; Hartmann, M.
Tetrahedron 1996, 52, 3229. Martin, S. F.; Limberakis, C.; Burgess, L. E.;
Hartmann, M. Tetrahedron 1999, 55, 3561.
(4) Various derivatives have been formed from geldanamycin: (a)
Rinehart, K. L.; McMillan, M. W.; Witty, T. R.; Tipton, C. D.; Shield, L.
S. Li, L. H.; Reusser, F. Bioorg. Chem. 1977, 6, 353. (b) Rinehart, K. L.;
Sobiczewski, W.; Honegger, J. F.; Enanoza, R. M.; Witty, T. R.; Lee, V.
J.; Shield, L. S.; Li, L. H.; Reusser, F. Bioorg. Chem. 1977, 6, 341. (c)
Schnur, R. C.; Corman, M. L J. Org. Chem. 1994, 59, 2581. Schnur, R. C.;
Corman, M. L.; Gallaschun, R. J.; Cooper, B. A.; Dee, M. F.; Doty, J. L.;
Muzzi, M. L.; Moyer, J. D.; DiOrio, C. I.; Barbacci, E. G.; Miller, P. E.;
O’Brien, A. T.; Morin, M. J.; Foster, B. A.; Pollack, V. A.; Savage, D. M.;
Sloan, D. E.; Pustilnik, L. R.; Moyer, M. P. J. Med. Chem. 1995, 38, 3806.
(d) Schnur, R. C.; Corman, M. L J. Labelled Compd. Radiopharm. 1994,
34, 529. (e) Zheng, F. F.; Kuduk, S. D.; Chiosis, G.; Munster, P. N.; Sepp-
Lorenzino, L.; Danishefsky, S. J.; Rosen, N. Cancer Res. 2000, 60, 2090.
(f) Mandler, R.; Dadachova, E.; Brechbiel, J. K.; Waldmann, T. A.;
Brechbiel, M. W. Bioorg. Med. Chem. Lett. 2000, 10, 1025. (g) Kuduk, S.
D.; Zheng, F. F.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky, S. J. Bioorg.
Med. Chem. Lett. 1999, 9, 1233. Kuduk, S. D.; Harris, C. R.; Zheng, F. F.;
Sepp-Lorenzino, L.; Ouerfelli, Q.; Rosen, N.; Danishefsky, S. J. Bioorg.
Med. Chem. Lett. 2000, 10, 1303.
(3) (a) De Boer, C.; Meulman, P. A.; Wnuk, R. J.; Peterson, D. H. J.
Antibiot. 1970, 23, 442. (b) Rinehart, K. L.; Sasaki, K.; Slomp, G.; Grostic,
M. F.; Olson, E. C. J. Am. Chem. Soc. 1970, 92, 7591.
10.1021/ol0068997 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/23/2000

Unlike the herbimycins and macbecin I, the methoxy-
quinone of geldanamycin requires the use of a pentasubsti-
tuted benzene precursor 1 (Scheme 1). The 1,4-disposed
methoxyls will be converted to the quinone carbonyls at a
later stage.2 The absence of a benzylic C-15 hydroxyl group
in geldanamycin makes the use of a benzyldehyde aldol
reaction, a step used previously for herbimycin and
macbecin,2b,c at that position problematic. Also the C-11
hydroxyl in geldanamycin, not being a methoxyl as with
herbimycin A and macbecin I, requires differential protection
at the C-11 and C-12 hydroxyls. The C-10 methyl will be
introduced through the unsaturated precursor 2 or using the
extended Wittig adduct shown below. Aldehyde 3 reacted
with the boron enolate of pyrone 4, an extension of our
recently disclosed report, gives the anti aldol product with
high selectivity.10 The new bis-p-methoxyphenylpyrone
allows for convenient removal following the aldol step. Ceric
ammonium nitrate (CAN) can now be used in the presence
of the arylnitro group for conversion to 2.
Scheme 1
Aldehyde 3 is constructed starting with 1,2,4-trimethoxy-
benzene 5 which was formylated and nitrated to give
benzaldehyde 6 (Scheme 2).11 Treatment with sodium
Scheme 2
In addition, the crystal structure of the Hsp90-geldanamycin
complex suggests modifications that may lead to enhanced
activity.8 Hsp90 binding and inhibition are thought to be
responsible for the ability of geldanamycin to significantly
and selectively lower levels of various oncogenic tyrosine
kinases including v-Src, Bcr/Abl, and ErbB-2.9 Importantly,
levels of serine/threonine-specific kinases, PKA and PKC,
remain uneffected. Initially geldanamycin was considered to
be a specific kinase inhibitor, yet no direct kinase interaction
could be established. These recent findings together with the
distinct structure of geldanamycin clearly warrant the
development of a total synthesis. We now report the synthesis
of the left-hand portion of the molecule that includes an
aromatic precursor to the methoxyquinone seco acid 1 and
a key asymmetric anti-selective glycolate aldol reaction using
diaryl-4-oxapyrone 4 to set the C-11, C-12 hydroxy, methoxy
functionality (Scheme 1).
(5) Antiviral: (a) Take, Y.; Inouye, Y.; Nakamura, S; Allaudeen, H. S.;
Kubo, A. J. Antibiot. 1989, 42, 107. Herbicidal: (b) Heisey, R. M.; Putnam,
A. R. J. Nat. Prod. 1986, 49, 859. (c) Heisey, R. M.; Putnam, A. R. J.
Plant Growth Regul. 1990, 9, 19. NO Synthase inhibition: (d) Joly, G. A.;
Ayers, M.; Kilbourn, R. C. FEBS Lett. 1997, 403, 40. T-cell suppression:
(e) Yorgin, P. D.; Hartson, S. D.; Fellah, A. M.; Scroggins, B. T.; Huang,
W. J.; Katsanis, E. J. Immunol. 2000, 164, 2915.
(6) Whitesell, L.; Shifrin, S. D.; Schwab, G.; Neckers, L. M. Cancer.
Res. 1992, 52, 1721.
(7) (a) Whitesell, L.; Mimnaugh, E. G.; De Costa, B.; Myers, C. E.;
Neckers, L. M. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 8324. (b) Prodromou,
C.; Roe, S. M.; O’Brien, R.; Ladbury, J. E; Piper, P. W.; Pearl, L. H. Cell
1997, 90, 65.
(8) (a) Stebbins, C. E.; Russo, A. A.; Schneider, C.; Rosen, N.; Hartl, F.
U.; Pavletich, N. P. Cell 1997, 89, 239. (b) Roe, S. M.; Prodromou, R. O.;
Ladbury, J. E.; Piper, P. W.; Pearl, L. H. J. Med. Chem. 1999, 42, 260.
(9) (a) June, C. H.; Fletcher, M. C.; Ledbetter, J. A.; Schieven, G. L.;
Siegel, J. N.; Phillips, A. F.; Samelson, L. E. Proc. Natl. Acad. Sci. U.S.A.
1990, 87, 7722. (b) Schnur, R. C.; Corman, R. J.; Gallaschum, R. J.; Cooper,
B. A.; Dee, J. L.; Doty, J. L.; Muzzi, M. L.; Moyer, J. D.; DiOrio, C. I.;
Barbacci, E. G. J. Med. Chem. 1995, 38, 3813. (c) Lawrence, D. S.; Niu,
J. Pharmacol. Ther. 1998, 77, 81.
borohydride produces a benzyl alcohol that was converted
to the stable and very hindered bromide 7.12 Gratifyingly
the Evan’s asymmetric alkylation with the S-propionylox-
azolidinone occurred with high selectivity and yield to
produce 8.13 Other strategies investigated to set this C-14
methyl stereocenter, asymmetric conjugate cuprate, and
(10) Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E. L.; Dalley, N.
K. Org. Lett. 2000, 2, 3035.
(11) Gilman, H.; Thirtle, J. R. J. Am. Chem. Soc. 1944, 66, 858.
(12) Newman, M. S.; Wotiz, J. H. J. Am. Chem. Soc. 1949, 71, 1292.
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
260
Org. Lett., Vol. 3, No. 2, 2001

diisopinocampeylcrotylborane addition reactions gave low
yields and selectivities.14 The difficulties were most likely
due to the steric effect of the bis-o-methoxyls, a functionality
unique to geldanamycin as mentioned above. The auxiliary
was removed by lithium borohydride, and the resultant
alcohol was converted to the cyanide 9 under Mitsunobu
conditions using acetone cyanohydrin.15 Reduction with
DIBAL followed by exposure to water gave aldehyde 3.
Synthesis of the new bis-4-methoxyphenylpyrone follows
the two step procedure reported previously for the diphenyl
substrate (Scheme 3).10 The trans stilbene 10 was dihydroxy-
lamine at low temperature and treated with aldehyde 3 to
generate alcohol 12 following peroxide hydrolysis.19 The
70% yield was obtained at 1:1.2 aldehyde to enolate
1
stoichiometry. The 15:1 selectivity was determined by H
NMR. The stereoinduction of the major anti isomer product
12 is in accord with the previous study where the aldehyde
approaches the E-enolate face, in a closed Zimmerman-
Traxler arrangement, opposite to the C-5 pyrone aryl group
which is adjacent to the ether oxygen.10 A crystal structure
was solved for the methylated form of alcohol 12 confirming
both the aldol stereochemistry and the C-14 methyl stereo-
center.20 Use of an acyclic glycolate as an alternative
approach would be problematic in that known auxiliaries
generally give syn products through Z-enolates.10,21 Also,
asymmetric dihydroxylation with osmium tetroxide works
very well for syn diols from E-olefins but is not selective
for applications with Z-alkenes leading to anti diols.22 In
addition, allylmetals are generally limited to Z-γ-alkoxy
reagents that give syn products.23 However, a notable
exception is a recent indium-mediated allyltin addition of
Marshall.24 To continue, methylation of 12 followed by
treatment with DIBAL produced the lactol 13. The lactol,
which is in equilibrium with the hydroxy-aldehyde, reacted
with methyl carbethoxymethylidine triphenylphosphorane in
high yield generating the E-unsaturated ester 14. The
p-methoxyphenyl functionality now allowed for easy removal
of the pyrone fragment using ceric ammonium nitrate in 93%
yield.25 The p-methoxybenzaldehyde byproduct was easily
removed by chromatography. While the pyrone is destroyed
at this point, it should be noted that it is produced in a
catalytic fashion in only two steps from stilbene using the
AD-mix reagent. Overall, the process converts the stilbene
syn diol to a specific, differentially protected anti diol
corresponding to the desired target. Protection of the C-12
hydroxyl as the TBS ether generated the unsaturated ester 2
to finish the sequence.
Scheme 3
Coupling with a larger fragment, which represents most
of the remaining geldanamycin features, was also facilitated
(18) (a) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71. (b) David,
S.; Thieffry, A.; Veyrieres, A. J. Chem. Soc., Perkin Trans. 1 1981, 1796.
(19) (a) Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993,
58, 147. (b) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org.
Chem. 1992, 57, 499. (c) Paterson, I.; Wallace, D.; Cowden, C. Synthesis
1998, 639.
(20) X-ray data: for the methyl ether of 12, orthorhombic space group
P212121, a ) 9.629(6), b ) 17.661(3), c ) 19.081(3), B ) 24.98(2.13)°, V
) 3245(2) Å, Z ) 4, independent data 3385 (Rint ) 0.0121) R1 ) 0.0505
[I >2σ(I)] (see Supporting Information).
(21) Syn examples: (a) Evans, D. A.; Bender, S. L.; Morris, J. J. Am.
Chem. Soc. 1988, 110, 2506. (b) Andrus, M. B.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 10420. Anti versions: (c) Evans, D. A.; Kaldor, S.
W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
7001. Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 57, 1961. Anti with R-benzyloxyaldehydes: (d) Li, Z.; Wu, R.;
Michalczyk, R.; Dunlap, R. B.; Odom, J. D.; Silks, L. A., III. J. Am. Chem.
Soc. 2000, 122, 386. With dihydroxyacetone: (e) List, B.; Lerner, R. A.;
Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395.
lated with catalytic osmium tetroxide-bis-dihydroquinine
complex using Sharpless’ AD-mix-R reagent to give S,S-11
in high yield and selectivity.16 Analysis of a Mosher’s ester
formed from 11 was used to confirm the enantioselectivity.17
Pyrone formation using dibutyltin oxide and tert-butyl
bromoacetate gave 4 in 80% isolated yield.18 The enolate
was formed using dicyclohexylboron triflate and triethy-
(14) Hruby, V. J.; Jarosinski, M. A.; Li, G. Tetrahedron Lett. 1993, 34,
2561. Williams, D. R.; Kissel, W. S.; Li, J. J. Tetrahedron Lett. 1998, 39,
8593.
(15) Wilk, B. Syn. Commun. 1993, 23, 2481. Tsunoda, T.; Uemoto, K.;
Nagino, C.; Kawamura, M.; Kaku, H.; Ito, S. Tetrahedron Lett. 1999, 40,
7355.
(16) Sharpless, K. B.; Amberg, W.; Bennami, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.; Kwong, H.; Morikawa, K.; Wang Z. Xu, D.; Zhang,
X. J. Org. Chem. 1992, 57, 2768.
(22) (a) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568.
(b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483.
(23) (a) Hoffmann, R. W.; Kemper, B. Tetrahedron Lett. 1980, 4883.
(b) Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett. 1987, 28,
139.
(17) Full details of the synthesis and reactivity of the new pyrone will
be reported shortly.
(24) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1995, 60, 1920.
(25) Johansson, R.; Samuelsson, B. Chem. Commun. 1984, 201.
Org. Lett., Vol. 3, No. 2, 2001
261

by the aldol intermediate 12. The requisite phosphonate 16
needed for this strategy was made in two steps from the
known protected glycerate methyl ester 1526 which was
reacted with p-methoxybenzyl trichloroacetimidate27 followed
by lithio methylphosphonate addition (Scheme 4).28
Scheme 5
Scheme 4
Diol 17 was formed by methylation, reduction, and
treatment with CAN in high overall yield (Scheme 5). A
one pot sequence was developed to generate the protected
terminal alcohol 18.29 Treatment with TBSCl and Hu¨nig’s
base followed by addition of methoxyethoxymethyl chloride
(MEMCl) and then tetra-n-butylammonium fluoride (TBAF)
produced 18 in 77% yield in one operation. Oxidation gave
aldehyde 19, which was then subjected to Horner-Emmons
coupling with â-ketophosphonate 16 under the Roush-
Masamune conditions.30 Enone 20 was isolated in 75% yield.
Both 2 and 20 now open up a variety of routes for the
completion of the final target. These will include additions
to set the methyl C-10 stereocenter and couplings to generate
the remaining trisubstituted olefin and the diene amide. The
C-10 methyl-trisubstituted olefin region has been troubling
in the past ansamycin routes but has been solved using
cuprate addition,2b,g aldol reaction,2c or directed hydroboration.2a
Intermediates 2 and 20 now allow for a number of these
and other routes to be explored to develop a more efficient
approach to the bottom domain of geldanamycin.
A key piece leading to the synthesis of the important
Hsp90 inhibitor geldanamycin has been made. An anti-
selective glycolate aldol reaction with a new bis-methoxy-
phenylpyrone, made using catalytic asymmetric dihydroxy-
lation, was used to set the C-11, C-12 stereocenters with
high selectivity. Removal of the pyrone was accomplished
using CAN allowing for the production of two key advanced
intermediates. Completion of the route and further studies
with nonnatural variants will be reported in due course.
Acknowledgment. We wish to thank the National
Institutes of Health (GM57275) and the Brigham Young
University Cancer Center for funding, Prof. N. Kent Dalley
for the crystallography, and Dr. Bruce Jackson for mass
spectrometry.
(26) Kruse, C. G.; Scheeren, H. W.; Balzarini, J.; DeClerq, E.; Hermkens,
P. H. H.; Van Maarsereen, J. H. J. Med. Chem. 1992, 35, 3223.
(27) Danishefsky, S. J.; Villalobos, A.; Patten, A. D.; Boisvert, L.; Audia,
J. E. J. Org. Chem. 1989, 54, 3738.
(28) Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahajis,
D. P.; Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4672.
(29) Sinha, S. C.; Keinan, E. J. Org. Chem. 1997, 62, 377.
(30) Roush, W. R.; Masamune, S.; Essenfield, A. P.; Davis, J. T. Choy,
W.; Blanchette, M. A. Tetrahedron Lett. 1984, 25, 2183.
Supporting Information Available: Experimental de-
tails, NMR, MS, and X-ray data for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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